Adenoviruses are the most common infectious causes of external ocular disease encountered worldwide by the practicing ophthalmologist, and yet they remain virtually untreatable. There are currently no antiviral agents available to eradicate virus from the eye or prevent its spread. Furthermore, the current use of steroids by some physicians in the treatment of adenovirus eye disease is highly controversial, mostly because of lack of clarity concerning their effectiveness. We have developed and established an animal model of adenovirus pathogenesis in the eye using the New Zealand rabbit, and have successfully used this model to develop and test potential antiviral agents effective against adenoviruses and the eye diseases they cause. In the upcoming renewal, we plan to use it to address further aspects of treatment, prevention and the mechanisms of pathogenesis of adenovirus eye disease. There are two specific aims. In the first, we plan to evaluate a very promising broad spectrum antiviral drug, HPMPC, a drug that is effective in vitro against both adenoviruses and herpesviruses. Part of the aim will be to establish high concentration, infrequent dosage regimens effective at treatment and prevention of adenovirus ocular disease. The second part will aim to understand the mechanisms by which this drug acts and the development of resistance to it. This will involve the isolation and characterization of adenovirus and HSV-1 mutants resistant to HPMPC so that we may identify the viral target of HPMPC, the mechanisms by which resistance to the agent develops, and the effect of such resistance upon the pathogenesis of these viruses in the eye. The second aim concerns two aspects of adenovirus ocular pathogenesis. In part one of this aim, we will use the animal model to address the use of topical steroids in the treatment, not only of the delayed onset aspect of adenoviral eye disease, but also of the acute viral replicative phase of the infection. The second part of this aim will be to investigate the mechanisms of host range extension of adenovirus type 5 to the New Zealand rabbit, the basis for our ocular model. From these studies, we hope to establish parameters important in the treatment, management and understanding of pathogenesis of eye disease caused by adenoviruses in humans.